The cause of idiopathic Parkinson's disease (PD), a debilitating disease that afflicts an estimated 1 percent of persons age 60 or older, remains unknown. In this application, we propose genetic epidemiological studies, genetic linkage studies, and candidate gene studies for PD. In the past four years, we have established a ulti-institutional research program that has collected 300 PD affected sibling pairs and extended families. Our linkage analyses to onset age revealed evidence for linkage (LOD 2.1) to chromosome 2pl3 at the 'PARK3' locus (Gasser et al. 1998). Recently, we found association (p<0.02) to the same STR marker and allele as seen by Dr. Gasser's group and association to SNP alleles (pC0.008) We also see evidence for linkage to two other loci reported by other groups. Our reported linkage to PD affection on chromosome 9q (DeStefano et al. 2001) is also reported by Scott et al. (2001). Drs. Hardy and Farrer of the Mayo Clinic Jacksonville confirm linkage to chromosome 10q in the same region that we reported for PD affection. Thus, we have detected at least three regions (2p, 9q, and 10q) that harbor PD related genes detected by other groups. These findings confirm that PD is a complex trait, requiring a large well-characterized sample for sufficient power to identify the implicated genes. We propose (AIM 1) genetic epidemiological studies aimed at identifying factors related to penetrance in PD by studying risk factors predicting onset age in sibling pairs who are widely discordant for onset age. This unique sample of sibling pairs permits novel analyses of factors related to penetrance. We propose (AIM 2) to continue our genetic linkage analysis, with a 10cM density genome scan in 350 affected sibling pairs and other family members; 300 of these affected sibling pairs have already been collected. We will assess possible genetic heterogeneity associated with risk factor involvement and PD family history. We have found significant modification of onset age. We propose (AIM 4) to follow-up those regions with evidence for linkage to PD affection or onset age in and additional 350 PD sib pairs to be collected in this study. We further propose association studies to localize candidate genes. Finally, we propose (AIM 5) a focused candidate gene study for PD, concentrating primarily on genes and genomic regions implicated in dystonia, due to overlapping clinical features of PD and dystonia. This project has great potential to expand our knowledge of the genetics of PD and to identify PD associated genes and risk factors and patterns for their interaction.